The human immunodeficiency virus-1 (HIV-1) is responsible for a global epidemic, with over 33 million infected people worldwide. The lifecycle of HIV-1 has been extensively studied in the hope of identifying a therapeutic intervention that blocks viral transmission or viability. As an example, the Highly Active Anti-Retroviral Therapy (HAART) is a therapeutic approach targeting one or more stages of the HIV-1 life cycle. Favorable clinical results with HAART have shown that targeting different stages of the viral life cycle simultaneously may reduce the viral evolutionary escape mechanism that leads to drug resistance. HAART has proven effective at delaying the onset of AIDS in HIV-positive individuals, but does not provide a cure for the infection itself.
Despite decades of research, no vaccine- or microbicide-based approaches for preventing HIV-1 transmission to non-infected individuals are yet available. Even within the current space of prospective microbicides, there are no examples of clinically used agents or combinations of agents that directly and specifically destroy mature HIV-1 particles before they gain entry to a target cell. In fact, the leading microbicidal candidate is based on tenofovir, a reverse-transcriptase inhibitor. Thus, at this time there is no known therapeutically effective agent that specifically prevents HIV-1 entry and irreversibly destroys the virus, e.g., a therapeutic agent that directly and specifically destroys mature HIV-1 particles before they gain entry to a target cell.
A mature HIV-1 virion is an approximately one-attoliter-sized bilayer-enveloped packet of cytoplasm stolen from the cell from which the virion budded, surrounding the RNA-containing nucleocapsid. HIV-1 enters target cells via interactions between the viral envelope protein spike, Env, with the surface-expressed CD4 receptor and a chemokine co-receptor (CCR5 or CXCR4). Env is a metastable heterotrimeric protein complex of three transmembrane gp41 subunits anchored to the viral membrane and three labile gp120 subunits that interface with gp41. The infection process starts with gp120 binding to CD4 and induction of a conformational change that exposes the co-receptor binding site. In turn, the fusion peptide sequence on gp41 inserts into the host membrane. Subsequently, gp41 transitions from a “pre-hairpin” complex into a collapsed, thermodynamically stable six-helix bundle, with the three N-terminal heptad repeats of each gp41 protomer forming the core and the three C-terminal heptad repeats folded into grooves along the outside of this core. This refolding process evidently brings the N- and C-termini of gp41 close together and, in so doing, brings the apposing membranes into close enough proximity that fusion is initiated. Spike-mediated fusion of viral and cellular membranes requires that one of its functions is to induce poration of viral membrane.
There is a need in the art to develop novel potent compositions that promote cell-free virolysis of HIV-1 virus. Such compositions would be useful for the prevention or treatment of HIV-1 infection. The present invention fulfills this need.